This invention relates to dioxy hexahydrobenzocycloheptaisoquinoline derivatives, to processes for preparing the derivatives, to pharmaceutical compositions thereof, and to methods for using the derivatives.
The dioxy derivatives have a 1,2,3,7,8,12b-hexahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinoline ring system and are characterized by having two adjacent oxy substituents on the aromatic carbocyclic portion of the isoquinoline moiety, namely at positions 4 and 5 or at positions 5 and 6.
Compounds having a 1,2,3,7,8,12b-hexahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinoline ring system have been reported: L. G. Humber and M. A. Davis, U.S. Pat. No. 3,403,157, Sept. 24, 1968 disclose such compounds wherein the ring system is optionally substituted with a variety of substituents at various positions; the compounds have antibacterial properties, the only reported activity. L. G. Humber et al., Canadian Pat. No. 1,000,701, Nov. 30, 1976 again disclose such compounds with a variety of optional substituents at various positions; the compounds are reported to be antibacterial agents and central nervous system depressants. None of the compounds claimed herein are exemplified in this patent which contains 192 pages and numerous specifically exemplified compounds. R. G. Simmonds, British Patent Specification No. 1,545,767, published May 16, 1979 discloses variously substituted 3-amino-1,2,3,7,8,12b-hexahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinoline derivatives having antiinflammatory and/or central nervous system activities. L. G. Humber et al., J. Heterocycl. Chem., 3, 247 (1966) report the preparation of 1,2,3,7,8,12b-hexahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinoline and its corresponding 4,5,10,11-tetramethoxy derivative. Also L. G. Humber et al., Can. J. Chem., 46, 2981 (1968) report a variety of N-substituted 1,2,3,7,8,12b-hexahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinolines, some of which have central nervous system activity.
In the preceding patents and publications, the 1,2,3,7,8,12b-hexahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinoline ring system is sometimes named according to a different chemical nomenclature. The chemical nomenclature used herein is the one which is currently more acceptable.
The dioxy derivatives of the present invention, characterized by their two adjacent oxy substituents, possess a valuable antipsychotic activity. Namely, the derivatives exert a neuroleptic action which is free of the extrapyramidal syndrome, a side effect usually associated with most neuroleptics. This surprising and unusual pharmacologic profile, combined with a lower order of toxicity, renders the derivatives as desirable agents for the treatment of schizophrenia.